학술논문
Nonstable Staphylococcus aureus Small-Colony Variants Are Induced by Low pH and Sensitized to Antimicrobial Therapy by Phagolysosomal Alkalinization.
Document Type
Academic Journal
Author
Leimer N; Division of Infectious Diseases and Hospital Epidemiology.; Rachmühl C; Division of Infectious Diseases and Hospital Epidemiology.; Palheiros Marques M; Division of Infectious Diseases and Hospital Epidemiology.; Bahlmann AS; Division of Infectious Diseases and Hospital Epidemiology.; Furrer A; Division of Infectious Diseases and Hospital Epidemiology.; Eichenseher F; Institute of Food, Nutrition, and Health, ETH Zurich, Switzerland.; Seidl K; Division of Infectious Diseases and Hospital Epidemiology.; Matt U; Division of Infectious Diseases and Hospital Epidemiology.; Loessner MJ; Institute of Food, Nutrition, and Health, ETH Zurich, Switzerland.; Schuepbach RA; Division of Surgical Intensive Care, University Hospital Zurich, University of Zurich.; Zinkernagel AS; Division of Infectious Diseases and Hospital Epidemiology.
Source
Publisher: Oxford University Press Country of Publication: United States NLM ID: 0413675 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6613 (Electronic) Linking ISSN: 00221899 NLM ISO Abbreviation: J Infect Dis Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Staphylococcus aureus-infected patients treated with antibiotics that are effective in vitro often experience relapse of infection because the bacteria hide in privileged locations. These locations include abscesses and host cells, which contain low-pH compartments and are sites from which nonstable S. aureus small-colony variants (SCVs) are frequently recovered.
Methods: We assessed the effect of low pH on S. aureus colony phenotype and bacterial growth, using in vitro and in vivo models of long-term infection.
Results: We showed that low pH induced nonstable SCVs and nonreplicating persisters that are capable of regrowth. Within host cells, S. aureus was located in phagolysosomes, a low-pH compartment. Therapeutic neutralization of phagolysosomal pH with ammonium chloride, bafilomycin A1, or the antimalaria drug chloroquine reduced SCVs in infected host cells. In a systemic mouse infection model, treatment with chloroquine also reduced SCVs.
Conclusions: Our results show that the acidic environment favors formation of nonstable SCVs, which reflect the SCVs found in clinics. They also provide evidence that treatment with alkalinizing agents, together with antibiotics, may provide a novel translational strategy for eradicating persisting intracellular reservoirs of staphylococci. This approach may also be extended to other intracellular bacteria.
(© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)
Methods: We assessed the effect of low pH on S. aureus colony phenotype and bacterial growth, using in vitro and in vivo models of long-term infection.
Results: We showed that low pH induced nonstable SCVs and nonreplicating persisters that are capable of regrowth. Within host cells, S. aureus was located in phagolysosomes, a low-pH compartment. Therapeutic neutralization of phagolysosomal pH with ammonium chloride, bafilomycin A1, or the antimalaria drug chloroquine reduced SCVs in infected host cells. In a systemic mouse infection model, treatment with chloroquine also reduced SCVs.
Conclusions: Our results show that the acidic environment favors formation of nonstable SCVs, which reflect the SCVs found in clinics. They also provide evidence that treatment with alkalinizing agents, together with antibiotics, may provide a novel translational strategy for eradicating persisting intracellular reservoirs of staphylococci. This approach may also be extended to other intracellular bacteria.
(© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)